1. Field of the Invention
The present invention relates to novel methods for the synthesis of N-cyclic maleimide acids and N-cyclic maleimide derivatives, and to novel N-cyclic maleimide acids and N-cyclic maleimide derivatives formed thereby.
2. Description of the Related Art
There are many known N-cyclic maleimide derivatives which are fluorescent substances. At present, such materials are widely used for the detection of nucleic acids, proteins, etc. In addition, these N-cyclic maleimides have many applications, such as use as monomers for raw materials in the chemical process industry. There is, therefore, an increasing demand for N-cyclic maleimide compounds.
Various techniques for the synthesis of maleimide derivatives have heretofore been proposed, all of which, however, result in low yields of maleimide derivatives.
Among the conventional methods for the synthesis of maleimide derivatives, a first method comprises reacting maleic anhydride with amines in ether to obtain a nearly quantitative yield of the corresponding N-substituted maleimide acid. Then, acetic anhydride and sodium acetate are added to the resulting maleamic acid, followed by heating at 100.degree. C. for dehydration to obtain the corresponding maleimide derivatives at a yield of 50 to 70% (see Mehta et al., J. Org. Chem., 1960, 25, 1012).
A second method comprises reacting maleic anhydride with an appropriate amino compound in ether to obtain a nearly quantitative yield of the corresponding maleamic acid. This is followed by heating under reflux in a mixture of triethylamine and toluene for dehydration of the maleamic acid to obtain the corresponding maleimide at a yield of 20% (see Meyers et al., J. Org. Chem., 1989, 54, 4243).
A third method comprises reacting maleic anhydride with an appropriate amino compound in ether to obtain a nearly quantitative yield of the corresponding maleamic acid, and then adding thereto a carbodiimide to obtain an isoimide. This is followed by heating the resulting isoimide in a mixture of hydroxybenzotriazole and toluene for 18 hours at 100.degree. C., to obtain the corresponding maleimide at a yield of 47% (see Garner et al., J. Org. Chem., 1991, 55, 5893).
A fourth method comprises reacting maleic anhydride with an amino compound in ether to obtain a nearly quantitative yield of the corresponding maleamic acid. This is then reacted with dicyclohexylcarbodiimide in a solvent of acetic acid and dimethylformamide for dehydration of the maleamic acid to obtain the corresponding maleimide at a yield of 75% (see Nielsen et al., Synthesis, 1991, 819).
The above-described methods are, however, not suitable for the synthesis of aliphatic maleimide derivatives. Furthermore, these methods result in N-cyclic maleimides of low yield.
A fifth method comprises reacting a maleimide with an aliphatic alcohol in a mixture of diisopropyl azodicarboxylate and acetic acid at room temperature for 18 hours. The corresponding aliphatic maleimide derivatives are obtained at a yield of from 83 to 92% (see Walker, J. Org. Chem., 1995, 60, 5352). This method is suitable for the synthesis of aliphatic maleimides, but could not be used for synthesizing N-aromatic maleimides.
A sixth method comprises an acid catalyzed dehydration of an amine and anhydride at reflux temperature. This results in the corresponding maleimide at a yield of 82% (see Yuichi Kita et al., Report in the 72nd Spring Meeting of the Chemical Society of Japan). The yield for this method is low. In addition, fluorescent aromatic maleimide derivatives synthesized according to this method provide low yields.
A seventh method comprises reacting maleic anhydride with an amine in benzene at room temperature, and then adding thereto hexamethyldisilazane, and zinc bromide or zinc chloride. This is followed by heating under reflux in benzene to obtain an aliphatic or benzyl-type maleimide at a yield of from 73 to 98% (see P. Y. Reddy, Toru et al., J. Org. Chem. in press). When fluorescent aromatic maleimides are synthesized according to this method, the starting compounds used remain in the reaction mixture without being reacted completely. This results in a low yield of maleimide derivatives.
As mentioned above, the conventional methods for synthesis of N-cyclic maleirnide derivatives are all problematic, and the yields associated therewith are low. In addition, some types of N-cyclic maleimides are difficult to produce thereby.